Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage

Soria, F.; Pérez-Samartı́n, Alberto; Martín, Abraham; Gona, Kiran; Llop, Jordi; Szczupak, Bogusław; Chara, Juan Carlos; Matute, Carlos; Domercq, Marı́a

doi:10.1172/jci71886

Cited by 110 publications

(120 citation statements)

References 76 publications

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“…It was found that the expression of the two subunits of this antiporter is reduced in patients with schizophrenia, which agrees with the hypo-glutamatergic neurotransmission hypothesis in the pathogenesis of this disease (Lin et al, 2015). However, an exacerbated activity of this antiporter may lead to glutamate excitotoxicity and neuronal death in ischemia (Soria et al, 2014). Also, higher expression of this subunit was found in glioma patients, and was associated with glutamate excitotoxicity, induced seizures and worse prognosis (Robert et al, 2015).…”

Section: Slc Transporterssupporting

confidence: 72%

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Esteras¹,

Dinkova‐Kostova²,

Abramov³

2016

Biological Chemistry

143

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Abstract:The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor wellknown for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

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Section: Slc Transporterssupporting

confidence: 72%

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Esteras¹,

Dinkova‐Kostova²,

Abramov³

2016

Biological Chemistry

143

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“…17 In addition, ischemic events result in overactivation of extrasynaptic NMDA receptors that result in neuronal death. 37 Thus, in ischemia, pannexins might generate a large inward current, producing the anoxic depolarization, either because of a direct-activating effect of ischemia on pannexin as seen in isolated pyramidal cells 18 or as a consequence of secondary channel opening produced by ischemia-evoked glutamate release.…”

Section: Discussionmentioning

confidence: 99%

Blockade of P2X7 Receptors or Pannexin-1 Channels Similarly Attenuates Postischemic Damage

Cisneros-Mejorado

Gottlieb

Cavaliere

et al. 2015

J Cereb Blood Flow Metab

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The role of P2X7 receptors and pannexin-1 channels in ischemic damage remains controversial. Here, we analyzed their contribution to postanoxic depolarization after ischemia in cultured neurons and in brain slices. We observed that pharmacological blockade of P2X7 receptors or pannexin-1 channels delayed the onset of postanoxic currents and reduced their slope, and that simultaneous inhibition did not further enhance the effects of blocking either one. These results were confirmed in acute cortical slices from P2X7 and pannexin-1 knockout mice. Oxygen-glucose deprivation in cortical organotypic cultures caused neuronal death that was reduced with P2X7 and pannexin-1 blockers as well as in organotypic cultures derived from mice lacking P2X7 and pannexin 1. Subsequently, we used transient middle cerebral artery occlusion to monitor the neuroprotective effect of those drugs in vivo. We found that P2X7 and pannexin-1 antagonists, and their ablation in knockout mice, substantially attenuated the motor symptoms and reduced the infarct volume to~50% of that in vehicle-treated or wild-type animals. These results show that P2X7 receptors and pannexin-1 channels are major mediators of postanoxic depolarization in neurons and of brain damage after ischemia, and that they operate in the same deleterious signaling cascade leading to neuronal and tissue demise.

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“…The searching of substances able to increase the resistance of animals to negative ischemia effect is assumed to consider the characteristics of of ischemic outcome [18,19], therefore, the resistance to ischemic damage in different lines of mice represents a topical issue for neurobiological researches [17,20,21]. Our study demonstrated С3Н line to be the most resistant to ischemic damage among all tested animals (C3H, CBA, SHK and C57BL/6).…”

Section: Animal Groupsmentioning

confidence: 72%

Adaptive Role of Glial Cell Line-Derived Neurotrophic Factor in Cerebral Ischemia

Митрошина¹,

Abogessimengane²,

Urazov³

et al. 2017

Sovrem Tehnol Med

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The aim of the investigation was to study the effect of glial cell line-derived neurotrophic factor (GDNF) on animals' resistance to cerebral-ischemia-induced damage.Materials and Methods. In vivo studies were carried out on C3H male mice weighing 18-40 g. Ischemia modeling was performed by bilateral irreversible occlusion of both carotid arteries. A neurological status as well as an orientative-exploratory behavior of experimental animals and their learning capability in the post-ischemic period were analyzed by using "Open field" and "Passive avoidance" tests. In addition, high-resolution respirometer Oxygraph-2k (Oroboros, Austria) was applied to study an oxygen uptake rate of brain mitochondria in ischemic conditions.Results. GDNF application in bilateral occlusion of carotid arteries was found to contribute to the neurological status recovery. Moreover, it normalizes oxygen uptake rate of mitochondria in the post-ischemic period.Conclusion. GDNF has a marked neuroprotective and antihypoxic effect under ischemia modeling in vivo.Key words: glial cell line-derived neurotrophic factor; GDNF; neuroprotection; cerebral ischemia. During several years the number of ischemic brain injury incidents has been dramatically increased, that determines topical and socially important issue for modern neurology and neuroscience. The consequences of cerebral ischemia are directly related to memory and neurological status deteriorations as well as to impairment of learning capabilities and cognitive functions. Therefore, the development of modern techniques to effectively protect the nervous system from those damaging effects is urgently needed. A promising approach to improve adaptive capabilities of nervous system supposed to the activation of endogenous systems promoting the survival of nervous cells under stress factors and maintenance their functional activity. The use of neurotrophic factors such as glial cell linederived neurotrophic factor (GDNF) is of special interest. These proteins are attracted of scientists' attention because of their possibilities to regulate neurogenesis and the functioning of the nervous cells not only in early ontogenesis, but also in an adult brain. Moreover, they are involved in the processes of synapses formation, and have a pronounced effect on growth Biomedical investigations

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Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage

Cited by 110 publications

References 76 publications

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Blockade of P2X7 Receptors or Pannexin-1 Channels Similarly Attenuates Postischemic Damage

Adaptive Role of Glial Cell Line-Derived Neurotrophic Factor in Cerebral Ischemia

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